Targeting OGG1 arrests cancer cell proliferation by inducing replication stress

Torkild Visnes, Carlos Benítez-Buelga, Armando Cázares-Körner, Kumar Sanjiv, Bishoy M F Hanna, Oliver Mortusewicz, Varshni Rajagopal, Julian J Albers, Daniel W Hagey, Tove Bekkhus, Saeed Eshtad, Juan Miguel Baquero, Geoffrey Masuyer, Olov Wallner, Sarah Müller, Therese Pham, Camilla Göktürk, Azita Rasti, Sharda Suman, Raúl Torres-RuizAntonio Sarno, Elisée Wiita, Evert J Homan, Stella Karsten, Karthick Marimuthu, Maurice Michel, Tobias Koolmeister, Martin Scobie, Olga Loseva, Ingrid Almlöf, Judith Edda Unterlass, Aleksandra Pettke, Johan Boström, Monica Pandey, Helge Gad, Patrick Herr, Ann-Sofie Jemth, Samir El Andaloussi, Christina Kalderén, Sandra Rodriguez-Perales, Javier Benítez, Hans E Krokan, Mikael Altun, Pål Stenmark, Ulrika Warpman Berglund, Thomas Helleday

Research output: Contribution to journalArticlepeer-review

Abstract

Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment.

Original languageEnglish
Article numbergkaa1048
JournalNucleic Acids Research
Early online date19 Nov 2020
DOIs
Publication statusE-pub ahead of print - 19 Nov 2020

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